Aminoglycoside antibiotics are a valuable class of therapeutic agents which include the gentamicins, neomycins, streptomicins, kanamycins and the more recently discovered fortimicins. It has been found that the antibacterial and pharmacological properties of many naturally produced aminoglycoside antibiotics can be altered by structural modifications to provide derivatives which are either less toxic than the parent antibiotic or with advantageously altered anti-bacterial spectrums which either have increased intrinsic activity against one or more organisms or increased activity against resistant strains.
Further, historically, once an aminoglycoside antibiotic has been in clinical use for a period of time, resistant microorganisms develop. In many cases, the resistance is R-factor mediated and is attributed to the ability of the bacteria to enzymatically modify the amino or hydroxyl groups of the aminoglycoside antibiotics. Thus, there is also a need for new entities which can be held in reserve to combat strains which have become resistant to treatment by the clinically used antibiotics.
The fortimicins are a relatively new class of aminoglycoside antibiotics. Fortimicin A is disclosed in U.S. Pat. No. 3,976,768 and fortimicin B in U.S. Pat. No. 3,931,400. Chemical modification of the parent fortimicins have been found to either increase the intrinsic activity against one or more microorganisms, reduce the toxicity or provide therapeutic agents which, while having about the same, or perhaps somewhat weaker activity than the parent compounds or other derivatives, nevertheless are useful as reserve antibiotics in the event resistant strains develop after a period of clinical use of one or more of the fortimicins.
The derivatives provided to date include the 4-N-acyl and alkyl derivatives of fortimicin B(U.S. Pat. No. 4,091,032); 3-O-demethylfortimicins A and B and derivatives (U.S. Pat. No. 4,124,756), 2-deoxyfortimicin B (U.S. Pat. No. 4,169,198); 2-deoxyfortimicin A and 4-N-fortimicin B derivatives (U.S. Pat. No. 4,192,867), 1-epi-derivatives of fortimicins A and B U.S. Pat. No. 4,218,441, and 2-epi-derivatives of fortimicins A and B (U.S. Ser. No. 25,036 filed Mar. 29, 1979), now abandoned.
While a number of fortimicin derivatives have been made to date, including the above mentioned ones, and valuable therapeutic agents identified, the search continues for new fortimicin derivatives which exhibit either a broader spectrum, less ototoxicity, oral activity or which can be held in reserve and used to treat infections caused by organisms which have become resistant to therapy with other fortimicins.
The present invention provides a new class of fortimicin derivatives.